OBJECTIVE: The primary objective of this project is to determine if supplementation with multiple vitamin-minerals reduces the incidence and mortality of esophageal cancer, gastric cancer, and total mortality. Secondary objectives are to assess supplement effects on intermediate endpoints in carcinogenesis and to examine new hypotheses relating to the etiology and prevention of esophageal cancer and gastric cancer. BACKGROUND: Probably the highest worldwide rates of esophageal cancer occur in Linxian, China where cumulative death rates to age 75 for this cancer exceed 20%. Widespread deficiencies of multiple nutrients are considered the most likely cause, but consumption of pickled vegetables, moldy foods and nitrosamines, and physical trauma from silica fragments in ingested millet may play a role. METHODS: Two double-blind, placebo-controlled randomized intervention studies were conducted to evaluate multiple vitamins/minerals in the prevention of esophageal and other cancers. The Dysplasia Trial evaluated 3,318 persons with cytologic evidence of dysplasia supplemented for 6 years, while the General Population Trial evaluated 29,584 persons supplemented for 5 1/4 years. Biologic specimens (blood, toenails, cytology and histology specimens) were collected periodically throughout the trials. PROGRESS: TRIALS - Both trials concluded in 1991, and results showed that the combination of beta-carotene/vitamin E/selenium significantly reduced total mortality, total cancer mortality, and stomach cancer incidence and mortality. Results from endoscopic and cytologic examinations suggested that multiple vitamins/minerals may decrease proliferation and enhance cytologic reversion to nondysplasia. POST-TRIAL FOLLOW-UP - Analysis of data from 10 years of post-intervention followup (through May 2001) indicate that, for the General Population Trial, the beneficial effects of the beta-carotene/vitamin E/selenium supplementation continued after termination of the intervention, and that the benefits were greater in the younger participants. None of the four factors tested influenced lung cancer death rates. ETIOLOGY STUDIES - A number of nested case-cohort studies relating baseline serum values of micronutrients, fumonisins, Helicobacter pylori, HPV, and EBV to cancer have recently been completed. Results of recent analyses have shown: (1) an especially strong association with increased risk for esophageal cancer and gastric cardia cancer among subjects with low serum selenium levels;(2) no relation of serum carotenoids with esophageal cancer or gastric cancer;(3) a strong association for low serum alpha-tocopherol levels and esophageal cancer risk;(4) a strong association between low tissue zinc levels and increased esophageal cancer risk;(5) increased risk for H pylori exposure for gastric cancer, both cardia as well as body;(5) no relation of fumonisin exposure with esophageal cancer risk;(6) an association between tooth loss and risk of esophageal cancer and gastric cancer;(7) associations between several genetic polymorphisms and risk of esophageal cancer and gastric cardia cancer;(8) increased risk of gastric noncardia cancer in persons with self-reported goiter;and (9) no relation for HPV 16, 18, or 73 serology and esophageal cancer or gastric cancer.